chr11-14885847-A-T

Variant names:

• chr11-14885847-A-T
• rs61495246
• NM_024514.5:c.296T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_024514.5(CYP2R1):​c.296T>A​(p.Leu99His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L99P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP2R1 NM_024514.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

CYP2R1 (HGNC:20580): (cytochrome P450 family 2 subfamily R member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into the active ligand for the vitamin D receptor. A mutation in this gene has been associated with selective 25-hydroxyvitamin D deficiency. [provided by RefSeq, Jul 2008]

PDE3B (HGNC:8779): (phosphodiesterase 3B) Enables 3',5'-cyclic-nucleotide phosphodiesterase activity. Involved in negative regulation of angiogenesis; negative regulation of cell adhesion; and negative regulation of lipid catabolic process. Located in membrane. Part of guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-14885847-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2R1	NM_024514.5	c.296T>A	p.Leu99His	missense_variant	Exon 2 of 5	ENST00000334636.10	NP_078790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2R1	ENST00000334636.10	c.296T>A	p.Leu99His	missense_variant	Exon 2 of 5	1	NM_024514.5	ENSP00000334592.5
CYP2R1	ENST00000532805.1	n.6T>A		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000465097.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.90		Loss of stability (P = 0.0471);
MVP		0.93
MPC		0.73
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.94
gMVP		0.88
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61495246; hg19: chr11-14907393;